title: Itch E3 ubiquitin ligase regulates large tumor suppressor 1 stability [corrected].
abstract: The large tumor suppressor 1 (LATS1) is a serine/threonine kinase and tumor suppressor found down-regulated in a broad spectrum of human cancers. LATS1 is a central player of the emerging Hippo-LATS suppressor pathway, which plays important roles in cell proliferation, apoptosis, and stem cell differentiation. Despite the ample data supporting a role for LATS1 in tumor suppression, how LATS1 is regulated at the molecular level remains largely unknown. In this study, we have identified Itch, a HECT class E3 ubiquitin ligase, as a unique binding partner of LATS1. Itch can complex with LATS1 both in vitro and in vivo through the PPxY motifs of LATS1 and the WW domains of Itch. Significantly, we found that overexpression of Itch promoted LATS1 degradation by polyubiquitination through the 26S proteasome pathway. On the other hand, knockdown of endogenous Itch by shRNAs provoked stabilization of endogenous LATS1 proteins. Finally, through several functional assays, we also revealed that change of Itch abundance alone is sufficient for altering LATS1-mediated downstream signaling, negative regulation of cell proliferation, and induction of apoptosis. Taking these data together, our study identifies E3 ubiquitin ligase Itch as a unique negative regulator of LATS1 and presents a possibility of targeting LATS1/Itch interaction as a therapeutic strategy in cancer.
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada K7L 3N6.
authors.forename: King Ching
authors.initials: KC
authors.lastname: Ho
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Zhou
authors.forename: Yi-Min
authors.initials: YM
authors.lastname: She
authors.forename: Alex
authors.initials: A
authors.lastname: Chun
authors.forename: Terry D
authors.initials: TD
authors.lastname: Cyr
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D019556:COS Cells; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D004795:Enzyme Stability / Q000235:genetics; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000628:therapy; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases; C092745:LATS1 protein, human; D017346:Protein Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease